Synthesis of isocoumarins through three-component couplings of arynes, terminal alkynes, and carbon dioxide catalyzed by an NHC-copper complex

Article abstract of DOI:10.1002/anie.201404692

A copper-catalyzed multicomponent coupling reaction between in situ generated ortho-arynes, terminal alkynes, and carbon dioxide was developed to access isocoumarins in moderate to good yields. The key to this CO₂-incorporating reaction was the use of a versatile N-heterocyclic carbene/copper complex that was able to catalyze multiple transformations within the three-component reaction.

Full text of DOI:10.1002/anie.201404692

Angewandte
Chemie
DOI: 10.1002/anie.201404692
Synthetic Methods
Synthesis of Isocoumarins through Three-Component Couplings of
Arynes, Terminal Alkynes, and Carbon Dioxide Catalyzed by an NHC–
Copper Complex**
Woo-Jin Yoo, Thanh V. Q. Nguyen, and Shu¯ Kobayashi*
Abstract: A copper-catalyzed multicomponent coupling reac-
tion between in situ generated ortho-arynes, terminal alkynes,
and carbon dioxide was developed to access isocoumarins in
moderate to good yields. The key to this CO2-incorporating
reaction was the use of a versatile N-heterocyclic carbene/
copper complex that was able to catalyze multiple trans-
formations within the three-component reaction.
reactions take advantage of the highly electrophilic nature of
ortho-arynes to undergo nucleophilic addition with a variety
of nucleophiles, followed by the subsequent interception of
the aryl anion intermediate with various electrophiles, to
generate 1,2-disubstituted arenes. Based on the highly
energetic nature of the aryne intermediate, it should be well
suited to serve as a key intermediate for multicomponent
coupling reactions involving CO2. For example, Yoshida et al.
reported CO2 incorporation reactions using arynes, with
imines[6] and amines[7] as nucleophilic partners to generate
I
socoumarins are an important class of lactones that are
found in numerous natural products with a wide range of
biological activities.[1] As such, there is continued interest in
the development of new synthetic strategies to prepare these
materials in an expedient manner.[2] One of the most
prevalent methods to construct the isocoumarin ring structure
is the intramolecular cyclization of ortho-alkynylbenzoic acid
derivatives.[3] The major limitation of this strategy is the
multistep synthetic route required to obtain these 2-alkynyl-
benzoic acids. The development of a multicomponent cou-
pling reaction would thus allow access to these heterocycles in
rapid and modular fashion.
benzoxazinones
and
anthranilic
acid,
respectively
(Scheme 1). Despite these seminal reports, very few examples
of multicomponent coupling reactions involving benzynes
and CO2 have been disclosed thus far.[8]
The chemical utilization of carbon dioxide (CO2) as a C1
feedstock and a reaction medium to access value-added
materials and fuels is attractive, as CO2 is a safe, inexpensive,
and readily available gas.[4] However, because of its intrinsic
kinetic and thermodynamic stability, the use of CO2 in
synthetic organic chemistry is challenging and limited. In
order to overcome these barriers, the strategic use of highly
energetic starting materials and/or intermediates, in conjuga-
tion with a catalyst, allows the development of useful
synthetic methodologies that can incorporate CO2 into
complex organic materials.
Scheme 1. Multicomponent coupling reactions with a) arynes and CO2
(Yoshida et al. 2006[6], 2008[7]), and b) terminal alkynes, arynes, and
CO2 (this work). TMS=trimethylsilyl, OTf=trifluoromethanesulfonate.
Arynes are highly unstable species that have found use as
reactive intermediates in a variety of multicomponent
À
À
carbon carbon and carbon heteroatom bond formation
In order to expand the synthetic possibilities of incorpo-
rating CO2 with reactive aryne intermediates, our strategy
involves the use of transition-metal catalysts to broaden the
choice for potential nucleophilic partners in these multi-
component coupling reactions. Herein, we report an N-
heterocyclic carbene (NHC) copper complex as a catalyst for
the three-component coupling reaction of 2-(trimethylsily-
l)aryl triflates, terminal alkynes, and CO2 to generate
isocoumarins in an efficient manner (Scheme 1).
processes.[5] In most cases, these multicomponent coupling
[*] Dr. W.-J. Yoo, T. V. Q. Nguyen, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Science
Research from the Japan Society for the Promotion of Science
(JSPS), the Global COE Program (Chemistry Innovation through
Cooperation of Science and Engineering), The University of Tokyo,
the Ministry of Education, Culture, Sports, Science and Technology
(MEXT) (Japan), and the Japan Science and Technology Agency
(JST). NHC=N-heterocyclic carbene.
We were initially inspired by the copper-catalyzed multi-
component coupling reactions of arynes with terminal alkynes
and various electrophiles.[9] The common reactive intermedi-
ate among these multicomponent reactions is the transient
ortho-alkynylaryl/copper complex 1. We anticipated that such
[10]
an intermediate could be intercepted by CO2 to generate
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404692.
copper carboxylate 2 or undergo an additional 5-exo-dig or 6-
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
phenylimidazol-2-ylidene) as the catalyst, we obtained the
desired heterocyclic compounds in moderate yield with
isocoumarin 4a as the major product (Table 2, entry 1). We
conducted the further optimization with [(IPr)CuCl] as the
catalyst and a reduced amount of base, and found that using
a mixed solvent system composed of MeCN and THF
Scheme 2. Assumed reaction of copper intermediate 1 with CO2.
endo-dig cyclization to furnish phthalides 3 or isocoumarins 4,
respectively (Scheme 2).
Table 2: Optimization of reaction conditions with [(IPr)CuCl] as a cata-
lyst.[a]
The starting point for our optimization studies was based
on the work by Zhang and co-workers,[9a] who accomplished
the multicomponent coupling reaction of arynes, terminal
alkynes, and allylic chlorides by using catalytic amounts of
copper iodide, 1,2-bis(diphenylphosphino)ethane (dppe), and
stoichiometric amounts of K2CO3 and CsF in MeCN at 608C.
We thus attempted the three-component coupling of phenyl-
acetylene (5a) and benzyne precursor 6a as the model
reaction (Table 1).
Entry
Solvent
T [8C]
CO2 [atm]
Yield [%][b]
3a
4a
1
2
3
4
5
6
7
8
MeCN
60
60
60
60
60
40
90
110
90
90
90
25
25
25
25
25
25
25
25
1
2
49
traces
MeCN, MePh
MeCN, DCM
MeCN, DME
MeCN, THF
MeCN, THF
MeCN, THF
MeCN, THF
MeCN, THF
MeCN, THF
MeCN, THF
5
5
4
5
1
2
39
50
66
45
68
40
Table 1: Initial study of the copper-catalyzed three-component coupling
of terminal alkyne 5a, 2-(trimethylsilyl)phenyl triflate (6a), and CO2.[a]
9
10
11
n.d.
15
40
1
2
70
64
Entry
Ligand
Base
CO2 [atm]
Yield [%][b]
3a 4a
[a] Reaction conditions: alkyne 5a (0.25 mmol), aryne precursor 6a
(0.38 mmol), [(IPr)CuCl] (0.025 mmol, 10 mol%), Cs2CO3 (0.75 mmol),
CsF (0.75 mmol) in solvent (1:1, 1 mL) at various temperatures under
CO2 pressure. [b] Yields based on 5a and determined by 1H NMR
analysis using 1,1,2,2-tetrachloroethane as an internal standard.
1
2
3
4
5
6
dppe
dppe
dppe
P(nBu)3
P(Cy)3
P(tBu)3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
1
25
25
25
25
25
n.d.
2
3
8
10
13
5
13
19
4
18
improved the reaction (Table 2, entries 2–5). We also varied
the reaction temperature and found that at 908C, the
selectivity toward the six-membered heterocycle 4a was
improved (Table 2, entries 6–8). In addition, we examined
the effect of CO2 pressure, and the multicomponent carbox-
ylation reaction occurred smoothly even at 15 atm (Table 2,
entries 9–11). Finally, we examined various N-heterocyclic
carbene/copper complexes, but found no significant improve-
ments over the commercially available catalyst [(IPr)-
CuCl].[13]
With the optimized conditions in hand, we examined the
substrate scope for the three-component coupling reaction of
terminal alkynes 5a–j, 2-(trimethylsilyl)phenyl triflate (6a),
and CO2 (Table 3). In general, the copper-catalyzed carbox-
ylation reaction occurred relatively smoothly with various
substituted terminal alkynes bearing electron-donating moi-
eties, furnishing the desired isocoumarins 4a–e in good yields
(Table 3, entries 2–5); the exception was the reaction with
ortho-substituted alkyne 5c (entry 3). When the electron-
deficient alkyne 5 f was examined as a nucleophile, the yield
was only modest (Table 3, entry 6). Other terminal alkynes,
bearing a naphthyl group (Table 3, entry 7), a heteroaromatic
substituent (entry 8), and a vinyl moiety (entry 9), were also
suitable coupling partners for the three-component reaction
with CO2. While terminal alkynes substituted by sp2-hybrid-
ized carbon atoms provided the desired carboxylated product
[a] Reaction conditions: alkyne 5a (0.25 mmol), aryne precursor 6a
(0.38 mmol), CuI (0.025 mmol, 10 mol%), ligand (0.025 mmol,
10 mol%), base (1.25 mmol), CsF (0.75 mmol) in MeCN (1 mL) at 608C
under CO2 pressure. [b] Yields based on 5a and determined by 1H NMR
analysis using 1,1,2,2-tetrachloroethane as an internal standard.
n.d.=not detected.
Initially, when we performed the three-component cou-
pling reaction, the expected product was not obtained.
Instead, we found 1,2-diphenyl alkyne, derived from the
copper-catalyzed addition of terminal acetylene 5a to the
in situ generated benzyne, as the major product (Table 1,
entry 1). Based on this result, we assumed that one atmos-
phere of CO2 was insufficient to induce carboxylation. By
increasing the CO2 pressure to 25 atm, the desired cyclized
products 3a and 4a were obtained (Table 1, entry 2). Moti-
vated by our previous experience with carboxylation reac-
tions,[11] we changed the base from K2CO3 to Cs2CO3, which
slightly improved the three-component coupling reaction
(Table 1, entry 3). Under the assumption that the carboxyla-
tion reaction would be favored with electron-rich copper
complexes, we surveyed various electron-rich phosphine
ligands, which slightly improved the yields of the desired
carboxylated products (Table 1, entries 4–6). Fortuitously,
when we examined [(IPr)CuCl][12] (IPr= 1,3-bis(diisopropyl)-
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Table 3: Substrate scope of the copper-catalyzed coupling reaction of
terminal alkynes 5a-j and 2-(trimethylsilyl)phenyl triflate (6a) under CO2
pressure (15 atm).[a]
Table 4: Substrate scope of the copper-catalyzed coupling of phenyl-
acetylene (5a) and 2-(trimethylsilyl)aryl triflates 6b–f under CO2 pressure
(15 atm).[a]
Entry Pre-arynes 6b–f Isocoumarins 4l–o
Yield [%][b]
Entry
R
Yield
[%][b]
Entry
R
Yield
[%][b]
(4:4’)[c]
1
2
72 (4a)
81 (4b)
6
7
52 (4 f)
74 (4g)
1
2
3
4
5
6
84
80
3
43 (4c)
8
55 (4h)
4
5
70 (4d)
68 (4e)
9
69 (4i)
33 (4j)
71 (1:1.1)
66 (1:1)
48 (1:1)
10[c]
[a] Reaction conditions: alkyne 5a–j (0.25 mmol), aryne precursor 6a
(0.38 mmol), [(IPr)CuCl] (0.025 mmol, 10 mol%), Cs2CO3 (0.75 mmol),
CsF (0.75 mmol) in MeCN/THF (1:1, 1 mL) at 908C under 15 atm of CO2
pressure. [b] Yields of isolated products 4a–j based on 5a–j.
[c] [(TPr)CuCl] (0.025 mmol) was used as the catalyst. TPr=1,4-bis(2,6-
diisopropylphenyl)-3-methyl-1,2,3-triazol-5-ylidene.
n.d.
in good to modest yields, the use of aliphatic terminal alkynes,
such as 5j, led to a low yield (Table 3, entry 10).[14]
Next, we investigated the copper-catalyzed multicompo-
nent carboxylation with phenylacetylene (5a) and various
substituted 2-(trimethylsilyl)aryl triflates 6b–f (Table 4).
When 4,5-disubstituted aryne precursors 6b,c were utilized
as substrates, the expected isocoumarins 4k,l were generated
in good yields (Table 4, entries 1 and 2). In addition, the
nucleophilic addition to the unsymmetrical ortho-aryne
intermediate showed poor regioselectivity, providing 4-sub-
stituted silyl triflates 4m–4o and 4m’–o’ as mixtures of
regioisomers with modest to good yields (Table 4, entries 3–
5). In order to improve the regioselectivity of the three-
component coupling reaction, we screened C6-substituted
silyl aryl triflate 6g (Table 4, entry 6). However, the desired
carboxylated product was not detected, presumably because
of the poor nucleophilicity of the expected sterically hindered
2,6-disubstituted copper intermediate.
In order to demonstrate the synthetic utility of the three-
component coupling reaction of 2-(trimethylsilyl)aryl tri-
flates, terminal alkynes, and CO2, we also performed this
copper-catalyzed carboxylation reaction on a gram scale
(Scheme 3).
Based on previous reports on multicomponent coupling
reactions with ortho-aryne intermediates,[9] a tentative mech-
anism is proposed in Scheme 4. Initially, the in situ formed
NHC–copper hydroxide or carbonate deprotonates terminal
alkyne 5 to generate copper acetylide A. Concurrently, the
fluoride-induced silyl elimination of 6 provides the reactive
ortho-benzyne B, and this electrophilic intermediate reacts
with A to furnish ortho-alkynyl copper complex C. Such
intermediates have been previously proposed for multicom-
[a] Reaction conditions: alkyne 5a (0.25 mmol), aryne precursor 6b–f
(0.38 mmol), [(IPr)CuCl] (0.025 mmol, 10 mol%), Cs2CO3 (0.75 mmol),
CsF (0.75 mmol) in MeCN/THF (1:1, 1 mL) at 908C under 15 atm of CO2
pressure. [b] Yields of isolated products 4k–o based on 5a. [c] Regioi-
someric ratios determined by 1H NMR analysis.
Scheme 3. Gram-scale synthesis of 3-substituted isocoumarin 4a.
ponent coupling reactions involving terminal alkynes and 2-
(trimethylsilyl)aryl triflates, and under our optimized reaction
conditions in the absence of CO2 led to the formation of
diphenylacetylene [Scheme 5, Eq. (1)]. Although the nucle-
ophilic addition of A to CO2 has been reported,[15] we
speculate that this unproductive pathway is disfavored
because of the strong electrophilicity of B. Next, ortho-
alknyl aryl copper complex C can undergo nucleophilic
addition to CO2 to generate copper carboxylate D,[12] which
would be followed by a 6-endo-dig cyclization to form
endocyclic copper heterocycle E. In order to validate the
proposed carboxylation–cyclization steps, the [(IPr)CuCl]-
catalyzed carboxylation of ortho-alkynylarylboronic ester 7
was performed [Eq. (2)]. This copper-catalyzed reaction,
which also involves C as an intermediate,[16] provided the
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
of the competition between the base-mediated 5-exo-dig and
the copper-catalyzed 6-endo-dig cyclization reactions of
metalated ortho-alkynylbenzoates. Indeed, the control
experiment in the absence of [(IPr)CuCl] showed that the
base-mediated cyclization reaction of 8 provides 3a as the
major regioisomer. Finally, we examined the three-compo-
nent coupling reaction with a deuterium-enriched alkyne [D]-
5a as a substrate and found that deuterium was not
incorporated into isocoumarin 4a. This result suggested that
the regeneration of the copper catalyst is most likely a result
of transmetalation between endocyclic copper heterocycle E
and the cesium salts found in the reaction mixture.
In conclusion, we have developed an efficient copper-
catalyzed three-component coupling reaction of terminal
alkynes, 2-(trimethylsilyl)aryl triflates, and CO2. We found
that a single NHC–copper complex possessed the ability to
facilitate multiple transformations within the multicompo-
nent reaction to deliver a wide range of substituted isocou-
marins in good yields. Further investigations into the synthetic
utility of ortho-arynes as reactive intermediates for CO2-
incorporating reactions are ongoing in our group.
Scheme 4. Proposed mechanism for the [(IPr)CuCl]-catalyzed three-
component reaction between alkynes, 2-(trimethylsilyl)aryl triflates, and
CO2.
Experimental Section
General procedure for the three-component coupling reaction
between terminal alkynes, ortho-aryne precursors, and CO2: In
a glove box with an inert atmosphere (Ar), [IPrCuCl] (12.0 mg,
0.025 mmol, 10 mol%), CsF (114.0 mg, 0.75 mmol), and Cs2CO3
(244.0 mg, 0.75 mmol) were weighed and placed into a stainless-
steel high-pressure reactor. Concurrently, a solution composed of 1-
alkyne 5 (0.25 mmol) and 2-(trimethylsilyl)aryl triflate 6 (0.38 mmol)
in MeCN/THF (1 mL, 1:1 v/v) was prepared in a screw-capped vial
(5 mL). After capping the high-pressure reactor with a rubber
septum, both the reaction vessel and the MeCN/THF solution were
removed from the glove box. The solution containing 5 and 6 was
transferred to the stainless steel reactor by syringe through the rubber
septum. The septum was quickly replaced with a stainless steel gas
line, and the reaction vessel was heated to 908C under 15 atm of CO2
for 24 h with magnetic stirring. Next, the high-pressure reactor was
allowed to cool to room temperature and the excess CO2 was vented.
After the addition of CH2Cl2 (20 mL) and a saturated NH4Cl solution
(10 mL) to the reaction mixture, the aqueous phase was extracted
twice with CH2Cl2 (2 ꢀ 10 mL) and the combined organic phase was
dried over Na2SO4. The solvent was removed under reduced pressure
and the crude mixture was purified using preparative TLC or column
chromatography (n-hexane/EtOAc, 10:1 v/v) to afford isocoumarins 4
as light-yellow solids.
Scheme 5. Support experiments for the proposed mechanism of the
copper-catalyzed carboxylation reaction to access 3-substituted isocou-
marins.
Received: April 25, 2014
Revised: June 21, 2014
Published online: && &&, &&&&
Keywords: alkynes · arynes · carbon dioxide · copper ·
multicomponent reactions
expected isocoumarin 4a as the major product. In addition,
we examined ortho-alkynylbenzoic acid 8 as a model sub-
strate for the intramolecular cyclization reaction [Eq. (3)],
and found that the expected cyclic lactone 4a was not
detected. Under the assumption that the interconversion
between C and D is reversible, we repeated the cyclization
reaction of 8 under CO2 atmosphere and found that the
heterocyclic compounds were obtained in an excellent yield,
albeit with phthalide 3a as the major product. This result
suggested that the origin of the product distribution is a result
.
[1] a) H. Matsuda, H. Shimoda, M. Yoshikawa, Bioorg. Med. Chem.
1999, 7, 1445 – 1450; b) J. H. Lee, Y. J. Park, H. S. Kim, Y. S.
Hong, K.-W. Kim, J. J. Lee, J. Antibiot. 2001, 54, 463 – 466; c) D.
Engelmeier, F. Hadacek, O. Hofer, G. Lutz-Kutschera, M. Nagl,
G. Wurz, H. Greger, J. Nat. Prod. 2004, 67, 19 – 25; d) W. Zhang,
K. Krohn, S. Draeger, B. Schulz, J. Nat. Prod. 2008, 71, 1078 –
1081.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[2] a) D. E. Korte, L. S. Hegedus, R. K. Wirth, J. Org. Chem. 1977,
42, 1329 – 1336; b) T. Izumi, Y. Nishimoto, K. Kohei, A.
Kasahara, J. Heterocycl. Chem. 1990, 27, 1419 – 1424; c) S. Cai,
F. Wang, C. Xi, J. Org. Chem. 2012, 77, 2331 – 2336; d) Z.-Y. Ge,
X.-D. Fei, T. Tang, Y.-M. Zhu, J.-K. Shen, J. Org. Chem. 2012, 77,
5736 – 5743; e) D. Nandi, D. Ghosh, S.-J. Chen, B.-C. Kuo, N. M.
Wang, H. M. Lee, J. Org. Chem. 2013, 78, 3445 – 3451.
[3] a) T. Sakamoto, M. An-naka, Y. Kondo, H. Yamanaka, Chem.
Pharm. Bull. 1986, 34, 2754 – 2759; b) H. Sashida, A. Kawamu-
kai, Synthesis 1999, 1145 – 1148; c) X. Li, A. R. Chianese, T.
Vogel, R. H. Crabtree, Org. Lett. 2005, 7, 5437 – 5440; d) M.
Uchiyama, H. Ozawa, K. Takuma, Y. Matsumoto, M. Yonehara,
K. Hiroya, T. Sakamoto, Org. Lett. 2006, 8, 5517 – 5520; e) C.
Kanazawa, M. Terada, Tetrahedron Lett. 2007, 48, 933 – 935; f) E.
Marchal, P. Uriac, B. Legouin, L. Toupet, P. van de Weghe,
Tetrahedron 2007, 63, 9979 – 9990; g) N. Sakai, K. Annaka, A.
Fujita, A. Sato, T. Konakahara, J. Org. Chem. 2008, 73, 4160 –
4165; h) B. Y.-W. Man, A. Knuhtsen, M. J. Page, B. A. Messerle,
Polyhedron 2013, 61, 248 – 252.
[4] For representative reviews on the use of CO2 as a C1 feedstock,
see: a) T. Sakakura, J.-C. Choi, H. Yasuda, Chem. Rev. 2007, 107,
2365 – 2387; b) K. Huang, C.-L. Sun, Z.-J. Shi, Chem. Soc. Rev.
2011, 40, 2435 – 2452; c) M. Cokoja, C. Bruckmeier, B. Rieger,
W. A. Herrmann, F. E. Kꢁhn, Angew. Chem. 2011, 123, 8662 –
8690; Angew. Chem. Int. Ed. 2011, 50, 8510 – 8537; d) Y. Tsuji, T.
Fujihara, Chem. Commun. 2012, 48, 9956 – 9964; e) X. Cai, B.
Xie, Synthesis 2013, 45, 3305 – 3324.
[8] a) S. Yoshida, T. Hosoya, Chem. Lett. 2013, 42, 583 – 585; b) T.
Kaicharla, M. Thangaraj, A. T. Biju, Org. Lett. 2014, 16, 1728 –
1731.
[9] a) C. Xie, L. Liu, Y. Zhang, P. Xu, Org. Lett. 2008, 10, 2393 –
2396; b) S. Bhuvaneswari, M. Jeganmohan, C.-H. Cheng, Chem.
Commun. 2008, 5013 – 5015; c) H. Yoshida, T. Morishita, H.
Nakata, J. Ohshita, Org. Lett. 2009, 11, 373 – 376; d) M.
Jeganmohan, S. Bhuvaneswari, C.-H. Cheng, Angew. Chem.
2009, 121, 397 – 400; Angew. Chem. Int. Ed. 2009, 48, 391 – 394;
e) F. Berti, P. Crotti, G. Cassano, M. Pineschi, Synlett 2012, 23,
2463 – 2468.
[10] a) J. Takaya, S. Tadami, K. Ukai, N. Iwasawa, Org. Lett. 2008, 10,
2697 – 2700; b) T. Ohishi, M. Nishiura, Z. Hou, Angew. Chem.
2008, 120, 5876 – 5879; Angew. Chem. Int. Ed. 2008, 47, 5792 –
5795; c) L. Dang, Z. Lin, T. B. Marder, Organometallics 2010, 29,
917 – 927; d) I. I. F. Boogaerts, G. C. Fortman, M. R. L. Furst,
C. S. J. Cazin, S. P. Nolan, Angew. Chem. 2010, 122, 8856 – 8859;
Angew. Chem. Int. Ed. 2010, 49, 8674 – 8677.
[11] W.-J. Yoo, M. Guiteras Capdevila, X. Du, S. Kobayashi, Org.
Lett. 2012, 14, 5326 – 5329.
[12] N-Heterocyclic carbene/copper complexes have been widely
utilized in chemical transformations involving CO2. For reviews,
see: a) L. Zhang, Z. Hou, Pure Appl. Chem. 2012, 84, 1705 –
1712; b) L. Zhang, Z. Hou, Chem. Sci. 2013, 4, 3395 – 3403.
[13] Additional information pertaining to our optimization studies
can be found in the Supporting Information.
[14] When [(IPr)CuCl] was used as a catalyst, 4j was obtained in only
24% yield, based on 5j and determined by 1H NMR analysis
using 1,1,2,2-tetrachloroethane as an internal standard.
[15] a) L. J. Gooßen, N. Rodrꢂguez, F. Manjolinho, P. P. Lange, Adv.
Synth. Catal. 2010, 352, 2913 – 2917; b) D. Yu, Y. Zhang, Proc.
Natl. Acad. Sci. USA 2010, 107, 20184 – 20189; c) K. Inamoto, N.
Asano, K. Kobayashi, M. Yonemoto, Y. Kondo, Org. Biomol.
Chem. 2012, 10, 1514 – 1516.
[5] For recent reviews on the use of arynes in organic synthesis, see:
a) A. Bhunia, S. R. Yetra, A. T. Biju, Chem. Soc. Rev. 2012, 41,
3140 – 3152; b) A. V. Dubrovskiy, N. A. Markina, R. C. Larock,
Org. Biomol. Chem. 2013, 11, 191 – 218; c) C. Wu, F. Shi, Asian J.
Org. Chem. 2013, 2, 116 – 125.
[6] H. Yoshida, H. Fukushima, J. Ohshita, A. Kunai, J. Am. Chem.
Soc. 2006, 128, 11040 – 11041.
[7] H. Yoshida, T. Morishita, J. Ohshita, Org. Lett. 2008, 10, 3845 –
3847.
[16] The formation of aryl N-heterocyclic carbene/copper complexes
as reactive intermediates through boron–copper transmetalation
has been reported for carboxylation reactions. Please see
reference [10b].
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
W.-J. Yoo, T. V. Q. Nguyen,
S. Kobayashi*
&&&& — &&&&
A facile synthetic protocol to isocoumar-
ins consists of a three-component cou-
pling reaction between 1-alkynes, 2-(tri-
methylsilyl)aryl triflates, and CO2 (see
scheme). The key to this reaction was the
use of a versatile N-heterocyclic carbene/
copper complex that was able to catalyze
multiple transformations within the
three-component reaction.
Synthesis of Isocoumarins through
Three-Component Couplings of Arynes,
Terminal Alkynes, and Carbon Dioxide
Catalyzed by an NHC–Copper Complex
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!